The discovery of small molecules capable of selectively modulating the activity of biological targets remains a central challenge of chemistry and chemical biology. Such small molecules are commonly discovered through combinatorial1,2 or diversity-oriented3 synthesis and high-throughput screening4 (HTS). In contrast, functional molecules emerge in nature through iterated cycles of translation, selection, and amplification with mutation.5-8 While scientists have applied components of biological evolution to generate DNA, RNA, and protein molecules with tailor-made catalytic or binding properties, this approach has traditionally been restricted to molecules whose structures are compatible with biosynthetic machinery.9-16 DNA-templated organic synthesis was recently developed as a method for translating DNA sequences into synthetic small molecules17-25 (see also published PCT application, WO 2004/016767) and synthetic polymers26-28 that can be subjected to in vitro selection for desired properties.17,20,23,28,29 Several related approaches to generate and evaluate DNA-encoded small-molecule libraries have also been used successfully in academic30-37 and industrial settings.38,39 
Macrocycles are particularly attractive candidates for the discovery of biologically active small molecules because their rigid scaffolds can decrease the entropic cost of target binding and limit access to non-binding conformations, resulting in higher affinity and greater binding specificity than their corresponding linear counterparts.40 In addition, macrocyclic peptide-like structures can offer advantages for applications in cell culture and in vivo over their linear analogs since they can possess higher bioavailability, membrane permeability, and resistance to in vivo degradation.40 While synthesizing macrocyclic structures, especially in a library format, can be challenging,41,42 features of DNA-templated synthesis including compatibility with aqueous solvents, extremely low (nM) reactant concentrations, and the ability of base pairing to hold together relevant reactants at high effective molarities can promote efficient macrocylization.